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Stimuli-responsive and targetable nanomedicine systems have been widely applied as effective modalities for drug delivery and tumor therapeutics. Particle shape is also important for the biodistribution and cellular uptake in drug delivery applications. Here, morphology tunable and acid-responsive dextran-doxorubicin conjugate assemblies of DD-M and DDF-V for targeted doxorubicin (DOX) delivery were constructed, which contain the following favorable advantages: (1) one-pot synthesis of the drug loaded system with a Schiff base reaction is a green chemistry method which is better than the conventional drug conjugation/encapsulation methods. (2) The morphology of the nanoparticles could be regulated from a micelle (DD-M) to vesicle (DDF-V) structure by either introducing folic acid (FA) or not. (3) The abundant hydroxyl groups and electronegativity give DD-M and DDF-V superior stability in the physiological environment. (4) Besides, the multifunctional DDF-V with its important merits including tumor-targeting ability and acid-responsiveness is specific for DOX delivery in cancer therapy. (5) Compared to free DOX and DD-M, DDF-V displayed enhanced anti-tumor efficacy both in vitro and in vivo without obvious systematic toxicity. The morphology tunable, acid-sensitive and targetable nanosystem could be a promising strategy for site-specific drug delivery and potential cancer therapy in the future.

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BACKGROUND: Insulin resistance (IR) is a common characteristic of women with polycystic ovary syndrome (PCOS). It has been reported that circulating Fetuin-A levels were associated with IR and type 2 diabetes mellitus (T2DM). However, previous reports were inconsistent. METHODS: Two hundred seven subjects were screened for PCOS according to the diagnostic guideline of the Rotterdam consensus criterion. Serum Fetuin-A levels were measured using an ELISA kit. An independent t-test or Nonparametric test was used to detect differences between PCOS and control groups. Spearman's correlation analysis was used to examine the association of the serum Fetuin-A with other parameters. RESULTS: Our findings showed that circulating Fetuin-A concentration ranged from 196.6 to 418.2 µg/L for most women without PCOS (95%). Women with PCOS had higher circulating Fetuin-A levels than healthy women (437.9 ± 119.3 vs. 313.8 ± 60.5 µg/L; p < 0.01). Serum Fetuin-A was positively correlated with BMI, WHR, TG, TC, LDL-C, HOMA-IR, LH, T, and DHEA-S. Multivariate regression analysis showed that WHR, TG, HOMA-IR, and DHEA-S were independent predictors of the levels of circulating Fetuin-A. Binary logistic regression revealed that serum Fetuin-A was associated with the occurrence of PCOS. In addition, our ROC curve analysis found that the cutoff values for Fetuin-A to predict PCOS and IR were 366.3 and 412.6 µg/L. CONCLUSION: Blood Fetuin-A may be a useful biomarker for screening women for PCOS and IR.

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Current standard of care dressings are unsatisfactorily inefficacious for the treatment of chronic wounds. Chronic inflammation is the primary cause of the long-term incurable nature of chronic wounds. Herein, an absorbable nanofibrous hydrogel is developed for synergistic modulation of the inflammation microenvironment to accelerate chronic diabetic wound healing. The electrospun thioether grafted hyaluronic acid nanofibers (FHHA-S/Fe) are able to form a nanofibrous hydrogel in situ on the wound bed. This hydrogel degrades and is absorbed gradually within 3 days. The grafted thioethers on HHA can scavenge the reactive oxygen species quickly in the early inflammation phase to relieve the inflammation reactions. Additionally, the HHA itself is able to promote the transformation of the gathered M1 macrophages to the M2 phenotype, thus synergistically accelerating the wound healing phase transition from inflammation to proliferation and remodeling. On the chronic diabetic wound model, the average remaining wound area after FHHA-S/Fe treatment is much smaller than both that of FHHA/Fe without grafted thioethers and the control group, especially in the early wound healing stage. Therefore, this facile dressing strategy with intrinsic dual modulation mechanisms of the wound inflammation microenvironment may act as an effective and safe treatment strategy for chronic wound management.

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OBJECTIVE: To develop an equation that can estimate the 24-h urinary Na excretion by using casual spot urine specimen for older hypertensive participants in rural Ningxia and further to compare with the INTERSALT method, Kawasaki method and Tanaka method. DESIGN: Older hypertensive participants in rural Ningxia provided their casual spot urine samples and 24-h urine samples between January 2015 and February 2017. Sex-specific equation was developed using linear forward stepwise regression analysis. Model fit was assessed using adjusted R2. Approximately half of all participants were randomly selected to validate the equation. Mean differences, intraclass correlation coefficients and Bland-Altman plots were used to evaluate the performance of all methods. SETTING: Pingluo County and Qingtongxia County in Ningxia Hui Autonomous Region, China. PARTICIPANTS: Older hypertensive participants in rural Ningxia. RESULTS: Totally, 807 of 1120 invited participants provided qualified 24-h urine samples and spot urine samples. There was no statistical difference comparing the laboratory-based method against the new method and the INTERSALT method, while Kawasaki method had the largest bias with a mean difference of 40·81 g/d (95 % CI 39·27, 42·35 g/d). Bland-Altman plots showed similar pattern of the results. CONCLUSION: The INTERSALT method and the new equation have the potential to estimate the 24-h urinary Na excretion in this study population. However, the extrapolation of the results to other population needs to be careful. Future research is required to establish a more reliable method to estimate 24-h urinary Na excretion.

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BACKGROUND: To report a case of a young patient with neurofibromatosis type 1 (NF1). METHODS: Here we review the treatment administered to a 7-year-old NF1 patient with neovascular glaucoma as the primary diagnosis. CASE PRESENTATION: A 7-year-old boy developed visual loss in the right eye associated with periocular pain and ipsilateral headache that had persisted for 1 week. The patient's condition did not improve after treatment with topical or systemic glaucoma medications. Fundus examination of the right eye showed superotemporal retinal vasoproliferative tumors (RVPT). Near-infrared reflectance scans of the left eye's fundus revealed bright patchy regions, scattered across the posterior pole; systemic examination showed café-au-lait spots all over the patient's body. The patient had a clear family history. Genetic testing confirmed NF1. The right eye was treated with intravitreal ranibizumab injection, retinal lesion cryotherapy, and transscleral ciliary body photocoagulation. After treatment, RVPT scarring was observed. The patient's intraocular pressure remained within normal limits. CONCLUSIONS: We report a rare case of neurofibromatosis in a pediatric patient with neovascular glaucoma accompanied by RVPT. We suggest that evaluations of young patients with neovascular glaucoma should include careful attention to the overall condition of the patient and his/her parents, as well as family history. If necessary, NF1 molecular testing should be performed to avoid a missed diagnosis or misdiagnosis.

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BACKGROUND: The influence of depression on the recurrence of atrial fibrillation (AF) after catheter ablation remains unclear. We performed a meta-analysis to evaluate the association between depression and AF recurrence after catheter ablation. METHODS: Cohort studies that evaluated depression at baseline and correlated depression with AF recurrence after catheter ablation were identified by searching the PubMed and Embase databases. Heterogeneity was determined using the Cochrane's Q test and calculating the I2 statistic. A random-effect model was applied to incorporate the potential influence of heterogeneity. RESULTS: Our analysis included seven cohort studies with 1,070 AF patients who underwent catheter ablation by circumferential pulmonary vein isolation. No significant heterogeneity was detected among the included studies (p for Cochrane's Q test = 0.20, I2 = 29%). Pooled results showed that depression before procedure was independently associated with increased risk of AF recurrence after catheter ablation (adjusted relative risk [RR]: 2.24, 95% confidence interval [CI]: 1.75 - 2.88, p < 0.001). Sensitivity analyses, conducted by omitting one study at a time, retrieved similar results (RR: 2.06 - 2.53, p all < 0.05). Predefined subgroup analyses showed that the association between depression and AF recurrence after catheter ablation was consistent regardless of the study characteristics, including study location, study design, patient number, type of AF, follow-up duration, adjustment of left atrial dimension, and quality score. LIMITATIONS: This analysis included a limited number of studies and various instruments applied to measure depression. CONCLUSIONS: Depression is an independent risk factor of AF recurrence after catheter ablation.

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The sensitive and accurate detection of cancer biomarkers is critically important to early clinical diagnosis, disease monitoring, and successful cancer treatment. Here, we first demonstrate an aptamer-based frequency shift Raman approach via sensing of graphene. This biosensor allows the rapid, sensitive, and label-free detection of the acknowledged protein cancer biomarker, prostate-specific antigen (PSA). Monolayer graphene is employed as the Raman substrate, which is highly sensitive to its electronic structure and interface properties. The PSA aptamer can be adsorbed strongly on the surface of substrates through π-π stacking interactions. The vibrational frequency of the G peak of graphene shifted upon the specific binding between the PSA and its aptamer. The corresponding frequency shifts of the G peak are directly correlated with PSA concentrations. The limit of detection is as low as 0.01 ng/mL, with a wide linear range from 0.05 ng/mL to 25 ng/mL. The analytic samples can be detected directly without any extensive preparation and label process. The whole detection is completed in only 30 min. Furthermore, excellent recoveries are acquired to validate the feasibility of this assay in human serum samples. The proposed technology could provide a selective, versatile, and user-friendly strategy for the early detection of cancer biomarkers.

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Affinity chromatography is a powerful technology for phosphopeptide enrichment from body fluids. Saliva is a non-invasive body fluid for disease diagnosis, while few studies applied affinity enrichment for saliva phosphoproteome. In this study, we tested two kinds of affinity chromatography materials, Ti4+-IMAC (immobilized metal affinity chromatography) and CaTiO3, for the enrichment of phosphopeptides. Through comparison, Ti4+-IMAC method was demonstrated as the superior one, which was utilized for the comprehensive analysis of salivary phosphoproteome. More than 360 phosphoproteins were specifically extracted and identified from human saliva. Ti4+-IMAC method was further applied to compare the phosphoprotein profiling in the saliva of lung cancer group and normal control group through label-free quantification. Accordingly, 477 and 699 phosphopeptides were enriched, respectively, which corresponded to 339 and 466 proteins. In total, 796 unique phosphopeptides were revealed for 517 saliva phosphoproteins. In particular, 709 phosphorylation sites were identified, among which 26 were up-regulated (>1.5) and 149 were down-regulated (<0.66) in lung cancer. Their corresponding proteins were mainly associated with cancer promotion, system disorder, and organismal injury. Our data collectively demonstrated that salivary phosphopeptides can be comprehensively characterized through Ti4+-IMAC method. These discovered phosphoprotein candidates might be used for lung cancer detection through salivary diagnostics.

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Crustaceans have a more persistent starvation tolerance than mammals, birds, reptiles, and even fish. This study is aimed at assessing the survival strategy and regulatory mechanism of crustaceans in response to starvation through an animal model using Eriocheir sinensis. In the 42-day starvation experiment, the hepatopancreas was found to become the target organ, which was characterized by atrophy of the thin wall in the hepatic tubules and expansion of the lumen. During short-term starvation, E. sinensis activates lipid and glycogen metabolism in the hepatopancreas with lipid metabolism dominating. In lipid metabolism, there was a significant decline in triglyceride, whereas cholesterol did not change significantly. Meanwhile, the fatty acid metabolism pathway was inhibited, but autophagy increased in the hepatopancreas, which may be the selective pathway for the decomposition of intracellular substances. However, under long-term starvation, the stored energy in the hepatopancreas was depleted, and E. sinensis selects to consume hepatopancreatic cells and maintain energy metabolism through apoptosis, which was triggered by both the death receptor pathway and the mitochondrial pathway. In addition, cell proliferation was blocked to reduce unnecessary energy consumption.

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OBJECTIVE: To investigate the effects of adjunct ketamine treatment on chronic treatment-resistant schizophrenia patients with treatment-resistant depressive symptoms (CTRS-TRD patients), including alterations in brain function. METHODS: Intravenous ketamine (0.5 mg/kg body weight) was administered to CTRS-TRD patients over a 1-hr period on days 1, 4, 7, 10, 13, 16, 19, 22, and 25 of our initial pilot study. This treatment method was subsequently repeated 58 days after the start of the pilot study for a secondary follow-up study. Calgary Depression Scale for Schizophrenia (CDSS), Positive and Negative Syndrome Scale (PANSS), and regional homogeneity (ReHo) results were used to assess treatment effects and alterations in brain function throughout the entire duration of our studies. RESULTS: Between day 7 and day 14 of the first treatment, CDSS scores were reduced by 63.8% and PANSS scores were reduced by 30.04%. In addition, ReHo values increased in the frontal, temporal, and parietal lobes. However, by day 21, depressive symptoms relapsed. During the second treatment period, CDSS and PANSS scores exhibited no significant differences compared to baseline between day 58 and day 86. On day 65, ReHo values were higher in the temporal, frontal, and parietal lobes. However, on day 79, the increase in ReHo values completely disappeared. CONCLUSIONS: Depressive symptoms in CTRS-TRD patients were alleviated with adjunct ketamine treatment for only 1 week during the first treatment period. Moreover, after 1 month, the antidepressant effects of ketamine on CTRS-TRD patients completely disappeared. Correspondingly, ReHo alterations induced by ketamine in the CTRS-TRD patients were not maintained for more than 3 weeks. These pilot findings indicate that adjunct ketamine treatment is not satisfactory for CTRS-TRD patients.

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Sirtuins (SIRTs) are NAD+-dependent lysine deacylases, regulating many important biological processes such as metabolism and stress responses. SIRT inhibitors may provide potential benefits against SIRT-driven human diseases. Development of efficient assay platforms based on fluorogenic substrates will facilitate the discovery of high-quality SIRT inhibitors. We here report 16 new fluorogenic peptide substrates (P1-P16) designed with structurally diverse tetrapeptides and acyl modifications. Tests of P1-P16 against SIRT isoforms identified several sensitive substrates for SIRT1, SIRT2, SIRT3 and SIRT5, which manifested lower KM values and higher catalytic efficiency, and particularly had less signal interference in inhibitor screening compared with our previously reported internally quenched fluorescent substrates. Co-crystallization of sensitive substrates P13 and P15 with SIRT5 revealed an unexpected binding mode, involving interactions with residues from active site bordering surfaces, different from that observed for other peptides derived from natural protein substrates. By using SIRT5 sensitive substrates, we found that TW-37, a Bcl-2 inhibitor, displayed low micromolar inhibition to SIRT5, which was further validated by isothermal titration calorimetry analyses, offering a new point to develop dual-action SIRT5/Bcl-2 inhibitors against cancers. This work provides assay platform and structural basis for developing new substrates and inhibitors targeting human SIRTs.

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Define changes in the visual cortex and retina in first-episode schizophrenia patients with visual disturbance (FUSCHVD) accompanied by antipsychotic agent treatment is important for guiding treatment. We examined the visual system prior to and after 3 years of antipsychotic-agent treatment in 48 patients with FUSCHVD and 50 healthy controls, and after 3.5 years of antipsychotic-agent treatment in 12 patients with FUSCHVD and 12 healthy subjects who came from the cohort with 3 years of follow up. Reduction of the visual cortex gray matter volume (GMV) was observed in patients compared to healthy controls, and impairments deteriorated accompanied with 3 years' treatment with antipsychotic agents. Total retinal thickness was also reduced in patients but did not deteriorated with treatment with antipsychotic agents. However, in the 12 patients who performed the additional 6-month follow-up, GMV and total retinal thickness reductions did not demonstrate any further trend in deterioration. These findings indicate that the reductions of GMV and retinal thickness may be self-limited. Although these findings were consistent with previous reports, it was only observed in a small number of patients. Therefore, clinicians should remain pay greater attention to visual system impairment in FUSCHVD.

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BACKGROUND: A routine blood examination is one of the most rapid, convenient and inexpensive clinical examinations that can reflect a patient's inflammatory status and other blood conditions, and the prognostic value of routine preoperative blood parameters in MIBC patients is still unclear, so we evaluated the prognostic value of routine preoperative blood parameters in muscle-invasive bladder cancer (MIBC) following radical cystectomy (RC). METHODS: Data on 202 patients with MIBC who underwent RC at our institution were retrospectively collected between October 2007 and August 2018. The median preoperative neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and hemoglobin (HGB) values were used as cutoffs to form the low and high NLR, low and high PLR, and low and high HGB groups, respectively. The clinicopathologic characteristics of each group were compared by chi-square and t tests. Kaplan-Meier survival and multivariate Cox regression analyses were used to analyze prognosis. RESULTS: The median NLR, PLR and HGB values were 2.42, 112 and 125 g/L, respectively. Kaplan-Meier results showed that the low HGB group had poor progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). A high NLR and high PLR groups correlated only with poor OS. Multivariate Cox analyses showed that pathological T3/4 stage, positive lymph node status and low HGB were independent risk factors for PFS, CSS and OS, and age was the only independent risk factor for OS. CONCLUSION: Preoperative peripheral blood HGB is an independent risk factor for the prognosis of MIBC patients. These data suggest that HGB may be a useful prognostic marker for MIBC patients undergoing RC.

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Purpose: To characterize the lens morphology and to measure the clinical features of familial exudative vitreoretinopathy (FEVR) in children.Methods: Unique lens changes were observed in a cohort of children with FEVR from March 2015 to November 2017 using slit lamp examination and all the patients underwent cycloplegic refraction, ultrasound A and B, keratometry and fundus fluorescein angiography.Results: Twelve eyes of eight children with FEVR had unique lens changes. The contraction of the posterior capsule caused unique lens changes resulting in myopia in nine eyes of six children and astigmatism in eight eyes of five children. Retinal lesions in the affected eyes were all stage 1 to 2. Six eyes of three patients underwent lensectomy and intraocular lens implantation due to high anisometropia which could not be corrected by conventional optical correction. During lensectomy, the opacification in the posterior capsule was found to be due to the fibrous membrane that protruded into the anterior vitreous and not due to lens opacification. Three patients had bilateral lensectomy, in two of whom significant macular involvement was observed in one eye and in one of whom significant macular involvement was observed in both eyes. After surgery visual acuity (VA) improved obviously in two eyes without significant macular involvement and did not improve in the four eyes which had significant macular involvement. Among the five patients who did not have lensectomy, one patient was lost to follow-up and one patient had VA improved in both eyes without significant macular involvement. The other three patients did not have much change in VA.Conclusions: Clinicians should be aware that when a high myopia or astigmatism does not match the corneal curvature and the length of the eye, one should check carefully the changes of lens and fundus after dilating the pupil, to avoid misdiagnosis and missed diagnosis.

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OBJECTIVES: To detemine preventive effects of compound formula Rhizoma Coptidis and Atractylodes on mice with gastric-ulcer. METHODS: The mice were randomly divided into a normal group, a gastric ulcer group, a ranitidine positive drug group, a Rhizoma Coptidis group, an Atractylodes group, and a Rhizoma Coptidis plus Atractylodes group (the ratios of Coptidis to Atractylodes were 9ê1, 8ê2, 7ê3, 6ê4, 5ê5, or 4ê6, respectively). Gastric ulcer models were established by intragastric administration of anhydrous ethanol after 6 days of preventive infusion. The mice were killed 6 days after the treatments. The whole stomach was opened to observe gross morphology of gastric mucosa. The pathological changes of gastric tissue were observed under microscope, and serum samples were collected to detect the contents of superoxide dimutase (SOD), malondialdehyde (MDA), NO, and endothelin-1 (ET-1). RESULTS: The Rhizoma Coptidis and Atractylodes decoction significantly decreased ulcer area (P<0.001), and the effects of compound formula are better than those of Coptidis and Atractylodes alone (P<0.05, P<0.01, or P<0.001). The anti-ulcer effect of compound formula (CoptidisêAtractylodes=6ê4) was the best one, and the anti-gastric ulcer effect of the high-dose group was significantly better than that of the ranitidine-positive group (P<0.001). The ranitidine positive drug group, the high-dose group of Rhizoma Coptidis, the high-dose group of Atractylodes, and the high-dose group of Rhizoma Coptidis-Atractylodes (6ê4) significantly reduced MDA, ET-1 (P<0.01 or P<0.001), and significantly increased SOD, NO in serum (P<0.01 or P<0.001). CONCLUSIONS: Rhizoma Coptidis and Atractylodes decoction exerts the effect on preventing ethanol-induced gastric ulcer in mice in a ratio-dependent and dose-dependent manner. The mechanism might be related to anti-oxidation and relaxion of blood vessels. The combination of the two drugs shows a synergistic effect.

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Schizophrenia is frequently accompanied by depressive symptoms, but the pathological mechanisms remain to be elucidated. In this study, we used chronic unpredicted mild stress plus MK801 injection to generate a mouse model of schizophrenia with depression, in which in vivo 2-photon calcium imaging and electrophysiological recordings were performed in conjunction with behavioral phenotyping. Compared to mice models with classical depression or to schizophrenia models, the animal models with schizophrenia and depression comorbidity presented worse psychotic and depressive symptoms. These behavioral deficits are associated with impaired neuronal calcium activities in the frontal cortex and thalamic nuclei. Moreover, in sharp contrast to classical models that have a satisfactory response to antipsychotic or antidepressant drugs, this novel schizophrenia with depression model is resilient to combined drug treatment in terms of behavioral and functional recovery. Taken together, these data indicate that schizophrenia with depression likely involves a unique pathophysiology that is different from schizophrenia or depression alone.

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OBJECTIVE: To study the changes in pulmonary function in infants and young children with Mycoplasma pneumoniae pneumonia (MPP). METHODS: A total of 196 hospitalized children (at age of 0-36 months) who were diagnosed with MPP from January 2014 to June 2018 were enrolled as study subjects. A total of 208 children (at age of 0-36 months) with pneumonia not caused by Mycoplasma pneumoniae infection during the same period of time were enrolled as controls (non-MPP group). A retrospective analysis was performed for their clinical data. The two groups were compared in the pulmonary function on the next day after admission and on the day of discharge. The children with MPP were followed up to observe pulmonary function at weeks 2 and 4 after discharge. RESULTS: Compared with the non-MPP group, the MPP group had significant reductions in the ratio of time to peak tidal expiratory flow to total expiratory time (TPTEF/TE), ratio of volume to peak tidal expiratory flow to total expiratory volume (VPTEF/VE), inspiratory-to-expiratory time ratio, and tidal expiratory flow at 25% remaining expiration on the next day after admission and on the day of discharge (P<0.05). In addition there were significant increases in the ratio of peak tidal expiratory flow to tidal expiratory flow at 25% remaining expiration, respiratory rate, effective airway resistance, and plethysmographic functional residual capacity per kilogram (P<0.05). Compared with the normal reference values of pulmonary function parameters, both groups had reductions in VPTEF/VE and TPTEF/TE on the next day after admission; on the day of discharge, the MPP group still had reductions in VPTEF/VE and TPTEF/TE, while the non-MPP group had normal values. The MPP group had increases in VPTEF/VE and TPTEF/TE from the day of discharge to weeks 2 and 4 after discharge (P<0.05), but TPTEF/TE still did not reach the normal value at week 4 after discharge. CONCLUSIONS: Airway obstruction is observed in infants and young children with acute MPP or non-MPP, and the children with MPP have a higher severity of airway obstruction and a longer time for improvement, with a certain degree of airway limitation in the recovery stage.

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Tetrabromobisphenol A (TBBPA) and its derivatives are the common flame-retardants that may increase the risk of development of many types of cancers, including liver cancer. However, the effects of TBBPA in the development and progression of liver cancer remains unknown. This study investigated the potential effects of TBBPA on a metastatic phenotype of hepatocellular carcinoma cell line-HepG2. Our results revealed that TBBPA significantly promoted the migration and invasion via affecting the number and distribution of lysosomes in HepG2 cells in a dose-dependent manner. Moreover, TBBPA decreased the intracellular protein levels of Beta-Hexosaminidase (HEXB), Cathepsin B (CTSB) and Cathepsin D (CTSD) while increased the extracellular CTSB and CTSD. It entailed that TBBPA exposure could promote the lysosomal exocytosis in cancer cells. The reversal results were obtained after adding lysosomal exocytosis inhibitor vacuolin-1. Docking results suggested that TBBPA could bind to TRPML1. It was consistent with the binding position of agonist ML-SA1. TRPML1 knockdown significantly decreased the invasion and migration, and the results were reversed when TBBPA was added. The results were indicated that TRPML1 was critical in lysosomal exocytosis. In addition, our results showed that TBBPA-TRPML1 complex regulated the calcium-mediated lysosomal exocytosis, thereby promoting the metastasis in liver cancer cells. It was expected that our data could provide important basis for understanding the molecular mechanism(s) of TBBPA promoting invasion and migration of hepatoma cells and give rise to profound concerns of TBBPA exposure on human health.

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